Mycophenolate Mofetil 500 Mg Powder For Concentrate For Solution For Infusion
Out of date information, search anotherSUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Mycophenolate mofetil 500 mg powder for concentrate for solution for infusion
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each vial contains the equivalent of 500 mg Mycophenolate mofetil (as hydrochloride salt).
For the full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Powder for concentrate for solution for infusion.
White to off white lyophilized powder. pH in the range of approximately 2.4 to 4.1 and osmolality in the range of approximately 300 to 340 mOsmol/Kg after reconstitution and dilution with 5 % glucose intravenous infusion solution at 6 mg/ml concentration.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Mycophenolate mofetil for infusion is indicated in combination with ciclosporin and corticosteroids for the prophylaxis of acute transplant rejection in patients receiving allogeneic renal or hepatic transplants.
4.2 Posology and method of administration
Treatment with Mycophenolate mofetil for infusion should be initiated and maintained by appropriately qualified transplant specialists.
CAUTION: MYCOPHENOLATE MOFETIL FOR INFUSION I.V. SOLUTION SHOULD NEVER BE ADMINISTERED BY RAPID OR BOLUS INTRAVENOUS INJECTION.
Mycophenolate mofetil for infusion is an alternative dosage form to Mycophenolate mofetil oral forms (capsules, tablets and powder for oral suspension) that may be administered for up to 14 days. The initial dose of Mycophenolate mofetil for infusion should be given within 24 hours following transplantation.
Following reconstitution to a concentration of 6 mg/ml, Mycophenolate mofetil for infusion must be administered by slow intravenous infusion over a period of 2 hours by either a peripheral or a central vein (see section 6.6).
Use in renal transplant: the recommended dose in renal transplant patients is 1 g administered twice daily (2 g daily dose).
Use in hepatic transplant: the recommended dose of Mycophenolate mofetil for infusion in hepatic transplant patients is 1 g administered twice daily (2 g daily dose). IV Mycophenolate mofetil for infusion should continue for the first 4 days following hepatic transplant, with oral Mycophenolate mofetil initiated as soon after this as it can be tolerated. The recommended dose of oral Mycophenolate mofetil in hepatic transplant patients is 1.5 g administered twice daily (3 g daily dose).
Use in children: safety and efficacy of mycophenolate mofetil in paediatric patients have not been established. No pharmacokinetic data with mycophenolate mofetil are available for paediatric renal transplant patients. No pharmacokinetic data are available for paediatric patients following hepatic transplants.
Use in elderly (> 65 years): the recommended dose of 1 g administered twice a day for renal or hepatic transplant patients is appropriate for the elderly.
Use in renal impairment: in renal transplant patients with severe chronic renal impairment (glomerular filtration rate < 25 mbmin-1*1.73 m-2), outside the immediate post-transplant period, doses greater than 1 g administered twice a day should be avoided. These patients should also be carefully observed. No dose adjustments are needed in patients experiencing delayed renal graft function post-operatively (see section 5.2). No data are available for hepatic transplant patients with severe chronic renal impairment.
Use in severe hepatic impairment: no dose adjustments are needed for renal transplant patients with severe hepatic parenchymal disease.
Treatment during rejection episodes: MPA (mycophenolic acid) is the active metabolite of Mycophenolate mofetil. Renal transplant rejection does not lead to changes in MPA pharmacokinetics; dosage reduction or interruption of Mycophenolate mofetil for infusion is not required. No pharmacokinetic data are available during hepatic transplant rejection.
For instructions on reconstitution and dilution of the medicinal product before administration, see section 6.6
4.3 Contraindications
Hypersensitivity reactions to mycophenolate mofetil have been observed (see section 4.8). Therefore, Mycophenolate mofetil for infusion is contraindicated in patients with a hypersensitivity to mycophenolate mofetil or mycophenolic acid.
Mycophenolate mofetil for infusion is contraindicated in patients who are allergic to polysorbate 80.
Mycophenolate mofetil for infusion is contraindicated in women who are breastfeeding (see section 4.6).
For information on use in pregnancy and contraceptive requirements, see section 4.6.
4.4 Special warnings and precautions for use
Patients receiving immunosuppressive regimens involving combinations of medicinal products, including Mycophenolate mofetil for infusion , are at increased risk of developing lymphomas and other malignancies, particularly of the skin (see section 4.8). The risk appears to be related to the intensity and duration of immunosuppression rather than to the use of any specific agent. As general advice to minimise the risk for skin cancer, exposure to sunlight and UV light should be limited by wearing protective clothing and using a sunscreen with a high protection factor.
Patients receiving Mycophenolate mofetil for infusion should be instructed to report immediately any evidence of infection, unexpected bruising, bleeding or any other manifestation of bone marrow depression.
Patients treated with immunosuppressants, including Mycophenolate mofetil for infusion, are at increased risk for opportunistic infections (bacterial, fungal, viral and protozoal), fatal infections and sepsis (see section 4.8). Such infections include latent viral reactivation, such as hepatitis B or hepatitis C reactivation and infections caused by polyomaviruses (BK virus associated nephropathy, JC virus associated progressive multifocal leukoencephalopathy PML) . Cases of hepatitis due to reactivation of hepatitis B or hepatitis C have been reported in carrier patients treated with immunosuppressants. These infections are often related to a high total immunosuppressive burden and may lead to serious or fatal conditions that physicians should consider in the differential diagnosis in immunosuppressed patients with deteriorating renal function or neurological symptoms.
There have been reports of hypogammaglobulinaemia in association with recurrent infections in patients receiving Mycophenolate mofetil in combination with other immunosuppressants. In some of these cases switching Mycophenolate mofetil to an alternative immunosuppressant resulted in serum IgG levels returning to normal. Patients on Mycophenolate mofetil for infusion who develop recurrent infections should have their serum immunoglobulins measured. In cases of sustained, clinically relevant hypogammaglobulinaemia, appropriate clinical action should be considered taking into account the potent cytostatic effects that mycophenolic acid has on T- and B-lymphocytes.
There have been published reports of bronchiectasis in adults and children who received Mycophenolate mofetil in combination with other immunosuppressants. In some of these cases switching Mycophenolate mofetil to another immunosuppressant resulted in improvement in respiratory symptoms. The risk of bronchiectasis may be linked to hypogammaglobulinaemia or to a direct effect on the lung. There have also been isolated reports of interstitial lung disease and pulmonary fibrosis, some of which were fatal (see section 4.8). It is recommended that patients who develop persistent pulmonary symptoms, such as cough and dyspnoea, are investigated.
Patients receiving Mycophenolate mofetil for infusion should be monitored for neutropenia, which may be related to Mycophenolate mofetil for infusion itself, concomitant medications, viral infections, or some combination of these causes. Patients taking Mycophenolate mofetil for infusion should have complete blood counts weekly during the first month, twice monthly for the second and third months of treatment, then monthly through the first year. If neutropenia develops (absolute neutrophil count < 1.3 x 103/pl) it may be appropriate to interrupt or discontinue Mycophenolate mofetil for infusion
Cases of pure red cell aplasia (PRCA) have been reported in patients treated with Mycophenolate mofetil in combination with other immunosuppressants. The mechanism for Mycophenolate mofetil induced PRCA is unknown. PRCA may resolve with dose reduction or cessation of Mycophenolate mofetil for infusion therapy. Changes to Mycophenolate mofetil for infusion therapy should only be undertaken under appropriate supervision in transplant recipients in order to minimise the risk of graft rejection (see section 4.8).
Patients should be advised that during treatment with Mycophenolate mofetil for infusion, vaccinations may be less effective, and the use of live attenuated vaccines should be avoided (see section 4.5). Influenza vaccination may be of value. Prescribers should refer to national guidelines for influenza vaccination.
Because mycophenolate mofetil has been associated with an increased incidence of digestive system adverse events, including infrequent cases of gastrointestinal tract ulceration, haemorrhage and perforation, Mycophenolate mofetil for infusion should be administered with caution in patients with active serious digestive system disease.
Mycophenolate mofetil is an IMPDH (inosine monophosphate dehydrogenase) inhibitor. On theoretical grounds, therefore, it should be avoided in patients with rare hereditary deficiency of hypoxanthine-guanine phosphoribosyltransferase (HGPRT) such as Lesch-Nyhan and Kelley-Seegmiller syndrome.
It is recommended that Mycophenolate mofetil for infusion should not be administered concomitantly with azathioprine because such concomitant administration has not been studied.
In view of the significant reduction in the AUC of MPA by cholestyramine, caution should be used in the concomitant administration of Mycophenolate mofetil for infusion with medicinal products that interfere with enterohepatic recirculation because of the potential to reduce the efficacy of Mycophenolate mofetil for infusion . Some degree of enterohepatic recirculation is anticipated following intravenous administration of Mycophenolate mofetil for infusion .
The risk: benefit of mycophenolate mofetil in combination with tacrolimus or sirolimus has not been established (see also section 4.5).
4.5 Interaction with other medicinal products and other forms of interaction
Interaction studies have only been performed in adults.
Aciclovir: higher aciclovir plasma concentrations were observed when Mycophenolate mofetil was administered with aciclovir in comparison to the administration of aciclovir alone. The changes in MPAG (the phenolic glucuronide of MPA) pharmacokinetics (MPAG increased by 8 %) were minimal and are not considered clinically significant. Because MPAG plasma concentrations are increased in the presence of renal impairment, as are aciclovir concentrations, the potential exists for Mycophenolate mofetil and aciclovir, or its prodrugs, e.g. valaciclovir, to compete for tubular secretion, and further increases in concentrations of both substances may occur.
Cholestyramine: following single dose, oral administration of 1.5 g of Mycophenolate mofetil to normal healthy subjects pre-treated with 4 g TID of cholestyramine for 4 days, there was a 40 % reduction in the AUC of MPA. (see section 4.4, and section 5.2). Caution should be used during concomitant administration because of the potential to reduce efficacy of Mycophenolate mofetil.
Medicinal products that interfere with enterohepatic circulation: caution should be used with medicinal products that interfere with enterohepatic circulation because of their potential to reduce the efficacy of mycophenolate mofetil.
Ciclosporin A: ciclosporin A (CsA) pharmacokinetics are unaffected by mycophenolate mofetil. In contrast, if concomitant ciclosporin treatment is stopped, an increase in MPA AUC of around 30% should be expected.
Ganciclovir: based on the results of a single dose administration study of recommended doses of oral mycophenolate and IV ganciclovir and the known effects of renal impairment on the pharmacokinetics of mycophenolate mofetil (see section 4.2) and ganciclovir, it is anticipated that co-administration of these agents (which compete for mechanisms of renal tubular secretion) will result in increases in MPAG and ganciclovir concentration. No substantial alteration of MPA pharmacokinetics is anticipated and mycophenolate mofetil dose adjustment is not required. In patients with renal impairment in which mycophenolate mofetil and ganciclovir or its prodrugs, e.g. valganciclovir, are co-administered, the dose recommendations for ganciclovir should be observed and patients should be monitored carefully.
Oral contraceptives: the pharmacokinetics and pharmacodynamics of oral contraceptives were unaffected by coadministration of mycophenolate mofetil (see also section 5.2).
Rifampicin: in patients not also taking ciclosporin, concomitant administration of mycophenolate mofetil and rifampicin resulted in a decrease in MPA exposure (AUC0-12h) of 18% to 70%. It is recommended to monitor MPA exposure levels and to adjust mycophenolate mofetil doses accordingly to maintain clinical efficacy when rifampicin is administered concomitantly.
Sirolimus: in renal transplant patients, concomitant administration of mycophenolate mofetil and CsA resulted in reduced MPA exposures by 30-50% compared with patients receiving the combination of sirolimus and similar doses of mycophenolate mofetil (see also section 4.4).
Sevelamer: decrease in MPA Cmax and AUC0-12 by 30% and 25%, respectively, were observed when mycophenolate mofetil was concomitantly administered with sevelamer without any clinical consequences (i.e. graft rejection). It is recommended, however, to administer mycophenolate mofetil at least one hour before or three hours after sevelamer intake to minimise the impact on the absorption of MPA. There is no data on mycophenolate mofetil with phosphate binders other than sevelamer.
Trimethoprim/sulfamethoxazole: no effect on the bioavailability of MPA was observed.
Norfloxacin and metronidazole: in healthy volunteers, no significant interaction was observed when mycophenolate mofetil was concomitantly administered with norfloxacin and metronidazole separately. However, norfloxacin and metronidazole combined reduced the MPA exposure by approximately 30 % following a single dose of mycophenolate mofetil.
Ciprofloxacin and amoxicillin plus clavulanic acid: Reductions in pre-dose (trough) MPA concentrations of about 50% have been reported in renal transplant recipients in the days immediately following commencement of oral ciprofloxacin or amoxicillin plus clavulanic acid. This effect tended to diminish with continued antibiotic use and to cease within a few days of their discontinuation. The change in predose level may not accurately represent changes in overall MPA exposure. Therefore, a change in the dose of mycophenolate mofetil should not normally be necessary in the absence of clinical evidence of graft dysfunction. However, close clinical monitoring should be performed during the combination and shortly after antibiotic treatment.
Tacrolimus: in hepatic transplant patients initiated on mycophenolate mofetil and tacrolimus, the AUC and Cmax of MPA, the active metabolite of mycophenolate mofetil, were not significantly affected by coadministration with tacrolimus. In contrast, there was an increase of approximately 20 % in tacrolimus AUC when multiple doses of mycophenolate mofetil (1.5 g BID) were administered to patients taking tacrolimus. However, in renal transplant patients, tacrolimus concentration did not appear to be altered by mycophenolate mofetil (see also section 4.4).
Other interactions: co-administration of probenecid with mycophenolate mofetil in monkeys raises plasma AUC of MPAG by 3-fold. Thus, other substances known to undergo renal tubular secretion may compete with MPAG, and thereby raise plasma concentrations of MPAG or the other substance undergoing tubular secretion.
Live vaccines: live vaccines should not be given to patients with an impaired immune response. The antibody response to other vaccines may be diminished (see also section 4.4).
4.6 Fertility, pregnancy and lactation
Pregnancy:
It is recommended that Mycophenolate mofetil for infusion therapy should not be initiated until a negative pregnancy test has been obtained. Effective contraception must be used before beginning Mycophenolate mofetil for infusion therapy, during therapy, and for six weeks following discontinuation of therapy (see section 4.5). Patients should be instructed to consult their physician immediately should pregnancy occur.
The use of Mycophenolate mofetil for infusion is not recommended during pregnancy and should be reserved for cases where no more suitable alternative treatment is available. Mycophenolate mofetil for infusion should be used in pregnant women only if the potential benefit outweighs the potential risk to the foetus. There is limited data from the use of mycophenolate mofetil in pregnant women. However, congenital malformations including ear malformations, i.e. abnormally formed or absent external/middle ear, have been reported in children of patients exposed to mycophenolate mofetil in combination with other immunosuppressants during pregnancy. Cases of spontaneous abortions have been reported in patients exposed to mycophenolate mofetil. Studies in animals have shown reproductive toxicity (see section 5.3).
Lactation:
Mycophenolate mofetil has been shown to be excreted in the milk of lactating rats. It is not known whether this substance is excreted in human milk. Because of the potential for serious adverse reactions to mycophenolate mofetil in breast-fed infants,
Mycophenolate mofetil for infusion is contraindicated in nursing mothers (see section 4.3).
4.7 Effects on ability to drive and use machines
No studies on the effects on the ability to drive and use machines have been performed. The pharmacodynamic profile and the reported adverse reactions indicate that an effect is unlikely.
4.8 Undesirable effects
The following undesirable effects cover adverse reactions from clinical trials:
The principal adverse reactions associated with the administration of mycophenolate mofetil in combination with ciclosporin and corticosteroids include diarrhoea, leucopenia, sepsis and vomiting, and there is evidence of a higher frequency of certain types of infections (see section 4.4). The adverse reaction profile associated with the administration of mycophenolate mofetil by intravenous infusion has been shown to be similar to that observed after oral administration.
Malignancies:
Patients receiving immunosuppressive regimens involving combinations of medicinal products, including mycophenolate mofetil, are at increased risk of developing lymphomas and other malignancies, particularly of the skin (see section 4.4). Lymphoproliferative disease or lymphoma developed in 0.6 % of patients receiving Mycophenolate mofetil (2 g or 3 g daily) in combination with other immunosuppressants in controlled clinical trials of renal (2 g data), cardiac and hepatic transplant patients followed for at least 1 year. Non-melanoma skin carcinomas occurred in 3.6 % of patients; other types of malignancy occurred in 1.1 % of patients. Three-year safety data in renal and cardiac transplant patients did not reveal any unexpected changes in incidence of malignancy compared to the 1-year data. Hepatic transplant patients were followed for at least 1 year, but less than 3 years.
Opportunistic infections:
All transplant patients are at increased risk of opportunistic infections; the risk increased with total immunosuppressive load (see section 4.4). The most common opportunistic infections in patients receiving mycophenolate mofetil (2 g or 3 g daily) with other immunosuppressants in controlled clinical trials of renal (2 g data), cardiac and hepatic transplant patients followed for at least 1 year were candida mucocutaneous, CMV viraemia/syndrome and Herpes simplex. The proportion of patients with CMV viraemia/syndrome was 13.5 %.
Elderly patients (> 65 years):
Elderly patients (> 65 years) may generally be at increased risk of adverse reactions due to immunosuppression. Elderly patients receiving Mycophenolate mofetil as part
of a combination immunosuppressive regimen, may be at increased risk of certain infections (including cytomegalovirus tissue invasive disease) and possibly gastrointestinal haemorrhage and pulmonary oedema, compared to younger individuals.
Other adverse reactions:
The following data refer to the safety experience of oral Mycophenolate mofetil in renal transplant patients. Data in hepatic transplant patients are based on i.v. dosing of Mycophenolate mofetil for up to 14 days followed by oral dosing. Adverse reactions, probably or possibly related to Mycophenolate mofetil, reported in >1/10 and in >1/100 to <1/10 of patients treated with Mycophenolate mofetil in the controlled clinical trials of renal (2 g data) and hepatic transplant patients are listed in the following table.
Adverse Reactions, Probably or Possibly Related to Mycophenolate mofetil, Reported in Patients Treated with mycophenolate mofetil in Renal and Hepatic Clinical Trials when Used in Combination with Ciclosporin and Corticosteroids
Within the system organ classes, undesirable effects are listed under headings of frequency, using the following categories: very common (>1/10); common (>1/100 to <1/10); uncommon (>1/1,000 to <1/100); rare (>1/10,000 to <1/1,000); very rare (<1/10,000), not known (cannot be estimated form the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
|
System organ class |
Adverse drug reactions | |
|
Infections and infestations |
Very common |
Sepsis, gastrointestinal candidiasis, urinary tract infection, herpes simplex, herpes zoster |
|
Common |
Pneumonia, influenza, respiratory tract infection, respiratory moniliasis, gastrointestinal infection, candidiasis, gastroenteritis, infection, bronchitis, pharyngitis, sinusitis, fungal skin infection, skin candida, vaginal candidiasis, rhinitis | |
|
Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
Very common |
- |
|
Common |
Skin cancer, benign neoplasm of skin | |
|
Blood and lymphatic system disorders |
Very common |
Leucopenia, thrombocytopenia, anaemia |
|
Common |
Pancytopenia, leucocytosis | |
|
Metabolism and nutrition disorders |
Very common |
- |
|
Common |
Acidosis, hyperkalaemia, hypokalaemia, hyperglycaemia, hypomagnesaemia, hypocalcaemia, hypercholesterolaemia, hyperlipidaemia, hypophosphataemia, anorexia | |
|
Psychiatric disorders |
Very common |
- |
|
Common |
Depression, thinking abnormal, insomnia | |
|
Nervous system disorders |
Very common |
- |
|
Common |
Convulsion, hypertonia, tremor, somnolence, headache, paraesthesia | |
|
Cardiac disorders |
Very common |
- |
|
Common |
Tachycardia | |
|
Vascular disorders |
Very common |
- |
|
Common |
Hypotension, hypertension | |
|
Respiratory, thoracic and mediastinal disorders |
Very common |
- |
|
Common |
Pleural effusion, dyspnoea, cough | |
|
Gastrointestinal disorders |
Very common |
Vomiting, abdominal pain, diarrhoea, nausea |
|
Common |
Gastrointestinal haemorrhage, peritonitis, ileus, colitis, gastric ulcer, duodenal ulcer, gastritis, oesophagitis, stomatitis, constipation, dyspepsia, flatulence | |
|
Hepatobiliary disorders |
Very common |
- |
|
Common |
Hepatitis | |
|
Skin and subcutaneous tissue disorders |
Very common |
- |
|
Common |
Rash, acne, alopecia, | |
|
Musculoskeletal and connective Tissue disorders |
Very common |
- |
|
Common |
Arthralgia | |
|
Renal and urinary disorders |
Very common |
- |
|
Common |
Renal impairment | |
|
General disorders and administration site conditions |
Very common |
- |
|
Common |
Oedema, pyrexia, chills, pain, malaise, asthenia, | |
|
Investigations |
Very common |
- |
|
Common |
Hepatic enzyme increased, blood creatinine increased, blood lactate dehydrogenase increased, blood alkaline phosphatase increased, weight decreased |
Note: 501 (2 g mycophenolate mofetil daily) and 277 (2 g IV / 3 g oral mycophenolate mofetil daily) patients were treated in Phase III studies for the prevention of rejection in renal and hepatic transplantation, respectively.
Adverse reactions attributable to peripheral venous infusion were phlebitis and thrombosis, both observed at 4 % in patients treated with mycophenolate mofetil by intravenous infusion.
The following undesirable effects cover adverse reactions from post-marketing experience:
Adverse reactions reported during post-marketing with Mycophenolate mofetil are similar to those seen in the controlled renal and hepatic transplant studies. Additional adverse reactions reported during postmarketing experience with mycophenolate mofetil are described below with the frequencies reported within brackets if known.
Gastrointestinal: gingival hyperplasia (>1/100 to <1/10), colitis including cytomegalovirus colitis, (>1/100 to <1/10), pancreatitis (>1/100 to <1/10) and intestinal villous atrophy.
Disorders related to immunosuppression: serious life-threatening infections including meningitis, endocarditis tuberculosis and atypical mycobacterial infection. Cases of BK virus associated nephropathy, as well as cases of JC virus associated progressive multifocal leucoencephalopathy (PML), have been reported in patients treated with immunosuppressants, including mycophenolate mofetil. Agranulocytosis (>1/1000 to <1/100) and neutropenia have been reported; therefore regular monitoring of patients taking mycophenolate mofetil is advised (see section 4.4). There have been reports of aplastic anaemia and bone marrow depression in patients treated with mycophenolate mofetil, some of which have been fatal.
Blood and lymphatic system disorder:
Cases of pure red cell aplasia (PRCA) have been reported in patients treated with mycophenolate mofetil (see section 4.4).
Isolated cases of abnormal neutrophil morphology, including the acquired Pelger-Huet anomaly, have been observed in patients treated with Mycophenolate mofetil. These changes are not associated with impaired neutrophil function. These changes may suggest a ‘left shift’ in the maturity of neutrophils in haematological investigations, which may be mistakenly interpreted as a sign of infection in immunosuppressed patients such as those that receive Mycophenolate mofetil.
Hypersensitivity: Hypersensitivity reactions, including angioneurotic oedema and anaphylactic reaction, have been reported.
Congenital disorders: see further details in section 4.6.
Respiratory, thoracic and mediastinal disorders:
There have been isolated reports of interstitial lung disease and pulmonary fibrosis in patients treated with mycophenolate mofetil in combination with other immunosuppressants, some of which have been fatal. There have also been reports of bronchiectasis in children and adults.
Immune system disorders:
Hypogammaglobulinaemia has been reported in patients receiving mycophenolate mofetil in combination with other immunosuppressants.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via
Yellow Card Scheme
Website: www.mhra.gov .uk/yellowcard
4.9 Overdose
Reports of overdoses with mycophenolate mofetil have been received from clinical trials and during post-marketing experience. In many of these cases, no adverse events were reported. In those overdose cases in which adverse events were reported, the events fall within the known safety profile of the medicinal product.
It is expected that an overdose of Mycophenolate mofetil could possibly result in oversuppression of the immune system and increase susceptibility to infections and bone marrow suppression (see section 4.4). If neutropenia develops, dosing with Mycophenolate mofetil for infusion should be interrupted or the dose reduced (see section 4.4).
Haemodialysis would not be expected to remove clinically significant amounts of MPA or MPAG. Bile acid sequestrants, such as cholestyramine, can remove MPA by decreasing the enterohepatic recirculation of the drug (see section 5.2).
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: immunosuppressive agents ATC code L04AA06
Mechanism of action
Mycophenolate mofetil is the 2-morpholinoethyl ester of MPA. MPA is a potent, selective, uncompetitive and reversible inhibitor of inosine monophosphate dehydrogenase, and therefore inhibits the de novo pathway of guanosine nucleotide synthesis without incorporation into DNA. Because T- and B-lymphocytes are critically dependent for their proliferation on de novo synthesis of purines whereas other cell types can utilise salvage pathways, MPA has more potent cytostatic effects on lymphocytes than on other cells.
5.2 Pharmacokinetic properties
Distribution
Following intravenous administration, mycophenolate mofetil undergoes rapid and complete metabolism to the active metabolite, MPA. The parent substance mycophenolate mofetil can be measured systemically during intravenous infusion. MPA at clinically relevant concentrations is 97 % bound to plasma albumin.
As a result of enterohepatic recirculation, secondary increases in plasma MPA concentration are usually observed at approximately 6 - 12 hours post-dose. A reduction in the AUC of MPA of approximately 40 % is associated with the coadministration of cholestyramine (4 g TID), indicating that there is a significant amount of enterohepatic recirculation.
Biotransformation
MPA is metabolised principally by glucuronyl transferase to form the phenolic glucuronide of MPA (MPAG), which is not pharmacologically active.
Elimination
A negligible amount of substance is excreted as MPA (< 1 % of dose) in the urine. Orally administered radiolabelled Mycophenolate mofetil results in complete recovery of the administered dose, with 93 % of the administered dose recovered in the urine and 6 % recovered in faeces. Most (about 87 %) of the administered dose is excreted in the urine as MPAG.
At clinically encountered concentrations, MPA and MPAG are not removed by haemodialysis. However, at high MPAG plasma concentrations (> 100pg/ml), small amounts of MPAG are removed.
In the early post-transplant period (< 40 days post-transplant), renal, cardiac and hepatic transplant patients had mean MPA AUCs approximately 30 % lower and Cmax approximately 40 % lower compared to the late post-transplant period (3 - 6 months post-transplant).
MPA AUC values obtained following administration of 1 g BID intravenous mycophenolate mofetil to renal transplant patients in the early post-transplant phase are comparable to those observed following 1 g BID oral mycophenolate mofetil. In hepatic transplant patients, administration of 1 g BID intravenous mycophenolate mofetil followed by 1.5 g BID oral mycophenolate mofetil resulted in MPA AUC values similar to those found in renal transplant patients administered 1 g mycophenolate mofetil BID.
Renal impairment:
In a single dose study (6 subjects/group), mean plasma MPA AUC observed in subjects with severe chronic renal impairment (glomerular filtration rate < 25 ml*min" '•1.73 m-2) were 28 - 75 % higher relative to the means observed in normal healthy subjects or subjects with lesser degrees of renal impairment. However, the mean single dose MPAG AUC was 3 - 6 fold higher in subjects with severe renal impairment than in subjects with mild renal impairment or normal healthy subjects, consistent with the known renal elimination of MPAG. Multiple dosing of mycophenolate mofetil in patients with severe chronic renal impairment has not been studied. No data are available for hepatic transplant patients with severe chronic renal impairment.
Delayed renal graft function:
In patients with delayed renal graft function post-transplant, mean MPA AUC (0-12h) was comparable to that seen in post-transplant patients without delayed graft function. Mean plasma MPAG AUC (0-12h) was 2 - 3-fold higher than in posttransplant patients without delayed graft function. There may be a transient increase in the free fraction and concentration of plasma MPA in patients with delayed renal graft function. Dose adjustment of Mycophenolate mofetil for infusion does not appear to be necessary.
Hepatic impairment:
In volunteers with alcoholic cirrhosis, hepatic MPA glucuronidation processes were relatively unaffected by hepatic parenchymal disease. Effects of hepatic disease on this process probably depend on the particular disease. However, hepatic disease with predominantly biliary damage, such as primary biliary cirrhosis, may show a different effect.
Elderly patients (> 65 years):
Pharmacokinetic behaviour of Mycophenolate mofetil in the elderly has not been formally evaluated.
Oral contraceptives:
The pharmacokinetics of oral contraceptives were unaffected by coadministration of mycophenolate mofetil (see also section 4.5). A study of the coadministration of mycophenolate mofetil (1 g bid) and combined oral contraceptives containing ethinylestradiol (0.02 mg to 0.04 mg) and levonorgestrel (0.05 mg to 0.15 mg), desogestrel (0.15 mg) or gestodene (0.05 mg to 0.10 mg) conducted in 18 nontransplant women (not taking other immunosupressants) over 3 consecutive menstrual cycles showed no clinically relevant influence of mycophenolate mofetil on the ovulation suppressing action of the oral contraceptives. Serum levels of LH, FSH and progesterone were not significantly affected.
5.3 Preclinical safety data
In experimental models, Mycophenolate mofetil was not tumourigenic. The highest dose tested in the animal carcinogenicity studies resulted in approximately 2 - 3 times the systemic exposure (AUC or Cmax) observed in renal transplant patients at the recommended clinical dose of 2 g/day.
Two genotoxicity assays (in vitro mouse lymphoma assay and in vivo mouse bone marrow micronucleus test) showed a potential of mycophenolate mofetil to cause chromosomal aberrations. These effects can be related to the pharmacodynamic mode of action, i.e. inhibition of nucleotide synthesis in sensitive cells. Other in vitro tests for detection of gene mutation did not demonstrate genotoxic activity.
Mycophenolate mofetil had no effect on fertility of male rats at oral doses up to 20 mg»kg"1»day"1. The systemic exposure at this dose represents 2 - 3 times the clinical exposure at the recommended clinical dose of 2 g/day. In a female fertility and reproduction study conducted in rats, oral doses of 4.5 mg*kg-1 ‘day-1 caused malformations (including anophthalmia, agnathia, and hydrocephaly) in the first generation offspring in the absence of maternal toxicity. The systemic exposure at this dose was approximately 0.5 times the clinical exposure at the recommended clinical dose of 2 g/day. No effects on fertility or reproductive parameters were evident in the dams or in the subsequent generation.
In teratology studies in rats and rabbits, foetal resorptions and malformations occurred in rats at 6 mg*kg-1 ‘day-1 (including anophthalmia, agnathia, and hydrocephaly) and in rabbits at 90 mg*kg-1*day-1 (including cardiovascular and renal anomalies, such as ectopia cordis and ectopic kidneys, and diaphragmatic and umbilical hernia), in the absence of maternal toxicity. The systemic exposure at these levels is approximately equivalent to or less than 0.5 times the clinical exposure at the recommended clinical dose of 2 g/day.
Refer to section 4.6.
The haematopoietic and lymphoid systems were the primary organs affected in toxicology studies conducted with mycophenolate mofetil in the rat, mouse, dog and monkey. These effects occurred at systemic exposure levels that are equivalent to or less than the clinical exposure at the recommended dose of 2 g/day. Gastrointestinal effects were observed in the dog at systemic exposure levels equivalent to or less than the clinical exposure at the recommended dose. Gastrointestinal and renal effects consistent with dehydration were also observed in the monkey at the highest dose (systemic exposure levels equivalent to or greater than clinical exposure). The nonclinical toxicity profile of Mycophenolate mofetil appears to be consistent with adverse events observed in human clinical trials which now provide safety data of more relevance to the patient population (see section 4.8).
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Mycophenolate mofetil for infusion : polysorbate 80 citric acid
hydrochloric acid sodium chloride
sodium hydroxide (for pH-adjustment).
6.2 Incompatibilities
Mycophenolate mofetil for infusion should not be mixed or administered concurrently via the same catheter with other intravenous medicinal products or infusion admixtures.
This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.
6.3 Shelf life
Powder for concentrate for solution for infusion: 2 years.
Reconstitution and dilution:
After reconstitution and dilution, chemical and physical in-use stability of solution for infusion has been demonstrated for 24 hours at 20 to 30 °C.
From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user.
6.4 Special precautions for storage
Powder for concentrate for solution for infusion: Do not store above 30°C.
For storage conditions after reconstitution and dilution of the medicinal product, see section 6.3.
6.5 Nature and contents of container
20 ml type I clear glass vials with grey butyl rubber stopper and aluminium flip off seal. Mycophenolate mofetil for infusion is available in packs containing either 4 vials or 1 vial.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
Preparation of Infusion Solution (6 mg/ml)
Mycophenolate mofetil for infusion does not contain an antibacterial preservative; therefore, reconstitution and dilution of the product must be performed under aseptic conditions.
Mycophenolate mofetil for infusion must be prepared in two steps: the first step is a reconstitution step with glucose intravenous infusion 5 % and the second step is a dilution step with glucose intravenous infusion 5 %. A detailed description of the preparation is given below:
Step 1
a. Two vials of Mycophenolate mofetil for infusion are used for preparing each 1 g dose. Reconstitute the content of each vial by injecting 14 ml of glucose intravenous infusion 5 %.
b. Gently shake the vial to dissolve the medicinal product yielding a slightly yellow solution.
c. Inspect the resulting solution for particulate matter and discoloration prior to further dilution. Discard the vial if particulate matter or discoloration is observed.
Step 2
a. Further dilute the content of the two reconstituted vials (approx. 2 x 15 ml) into 140 ml of glucose intravenous infusion 5 %. The final concentration of the solution is 6 mg/ml mycophenolate mofetil.
b. Inspect the infusion solution for particulate matter or discoloration. Discard the infusion solution if particulate matter or discoloration is observed.
If the infusion solution is not prepared immediately prior to administration, the commencement of administration of the infusion solution should be within 24 hours from reconstitution and dilution of the medicinal product. Keep solutions at 15 - 30° C.
Because Mycophenolate mofetil has demonstrated teratogenic effects in rats and rabbits, avoid direct contact of prepared solutions of Mycophenolate mofetil for infusion with skin or mucous membranes. If such contact occurs, wash thoroughly with soap and water; rinse eyes with plain water.
Any unused product or waste material should be disposed of in accordance with local requirements.
MARKETING AUTHORISATION HOLDER
Accord Healthcare Limited
Ground Floor, Sage House, 319 Pinner Road, North Harrow, Middlesex, HA1 4HF, United Kingdom
8 MARKETING AUTHORISATION NUMBER(S)
PL 20075/0395
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
09/03/2015
10 DATE OF REVISION OF THE TEXT
09/03/2015